By Nick Basta, Contributing EditorNo one doubts that better collaboration among departments within a pharmaceutical company, or between it and its business partners, is a good thing. The challenge, however, is to collaborate effectively, without creating more bureaucracy and endless meetings. There are two parts to solving this problem: having the right software tools to generate and organize information, and having the right work processes in place to make the best use of that information. A common feature of the latest software in planning and design is visualization, allowing users to see plant layouts, process flows, even the data involved in molecular design. The best work processes avoid repetitive data entry, requiring reliable ways to store and retrieve data, and allow it to flow seamlessly from one application to another. Collaborate or WitherHow important is collaboration? "The best companies in our industry are dramatically increasing the collaborations within the different parts of R&D, and dramatically increasing the collaboration between R&D, [manufacturing] and the supply chain" said Fred Hassan, CEO of Schering Plough (Kenilworth, N.J.) in an address at Princeton University last month. As part of an overall revamping of Schering-Plough, Hassan, who came on as CEO last year, has a multipronged improvement program going on within the company. Collaboration activities are part of what he calls "customer-centered product flow," which is meant to connect marketplace drivers in the industry more closely with manufacturing and R&D. "Interactions between R&D, the commercial organization and manufacturing were relatively infrequent until a compound was moved into development,and even then, the interactions might have been rare," says Hassan.This interface,where information is flowing between basic or clinical research and process design,is being addressed by software vendors on both sides of the divide. On the research side, companies like Accelrys (San Diego) are looking to use their molecular modeling programs and databases to address process considerations such as crystallization or formulation."The drug discovery process has two steps, from our perspective," says Keith Glassford, director, materials science marketing at Accelrys, "gene-to-lead, and lead-to-delivery." In the first step, Accelrys tools such as Cerius, a combinatorial-chemistry program, are used to help identify candidate compounds based on the reactivity and conformation of genetic or cellular targets, such as the surfaces of viruses. A biochemical insight into a new treatment results in a lead drug candidate which can then enter the rest of the drug discovery process.In lead-to-delivery, researchers are considering how to produce commercial quantities of the candidate, what its toxicity or interactions are in the human or other organism, and how to formulate an actual pharmaceutical product. Accelrys' tools include C2 MedChem Groupware for analyzing chemical structures; additional modules provide for modeling catalyzed reactions, visualization of the molecules or their cellular level, or "meso-scale" properties. Other programs, DPD and MesoDyn, analyze polymeric structures for drug delivery techniques.According to Keith, several other benefits come out of Accelrys' tools for managing drug discovery. One is C2 Polymorph, which can predict polymorphic forms of pharmaceutical crystals. This becomes important during the patent-application phase of drug discovery, when a lab wants to protect all the polymorphic forms of the compound under the patent. Finally, the MS Fast program, based on an Oracle database management system, allows labs to store previous experimental results, and to determine what battery of experiments needs to be performed to characterize a promising drug candidate. "Labs are often forced to repeat 20-30% of their experiments simply because necessary data wasn't properly recorded," notes Glassford. This kind of inefficiency is the opposite of an effective collaboration.So far, Glassford notes, it is rare for Accelrys products to be used by process engineers; however, the programs' capabilities are advancing, and their value in the process design stage is increasing. "Leading-edge companies know that these tools can speed up the lead-to-delivery stage of development, and that can make a significant impact on the bottom line."Accelrys provides fairly sophisticated tools for visualization of candidate molecules, and their reactions with catalysts or with biological surfaces or molecules. "It's a cliche, but a picture is worth 1,000 words to show stereochemical effects, and to communicate results between research, engineering and other groups," says Osman Gumar, executive director of Accelrys' cheminformatics and rational drug design group. "For process design considerations, our software can do things like visualize surface interactions in gases or on metal surfaces, which could affect materials selection." Visualize DesignWhen it comes to actual process design, being able to visualize the process is valuable, both in collaborative work and in meeting regulatory approval. Michael Grund, head of process engineering at Merck kGa (Darmstadt, Germany), uses the graphical and numeric output of a simulator to document a multipurpose batch plant, the largest in Europe, which has been built there over the past several years. "This has been a very complex process, with literally hundreds of different batch recipes needed to be reduced to a set of what we called 'design recipes,'" says Grund. "The documentation produced by the simulator helped us communicate with the project contractor, as well as to meet regulatory approvals."Merck uses BatchPlus, from Aspen Technology (Cambridge, Mass.). Dan Mekler, business development manager, says that BatchPlus has utility at "both ends of the design process, either to work with research chemists to figure out the feasibility of a process, or to develop process flows and capacities, and from that the equipment specifications, with the project contractor." On the laboratory side, a user can deploy a 'route selection and screener' feature to evaluate recipe alternatives. On the process design side, a 'scale up algorithm' is used to raise the output of the process to kilogram levels or beyond.Mekler adds that the company is currently working on a capability of loading data from the electronic lab notebooks frequently used in research directly into BatchPlus (or a related software tool, Batch.21, which is focused more on production scheduling), as a way to speed up the transfer of information into process development. "Everyone knows that the trend in this industry is to run the drug-discovery process more rapidly," he says. "Using BatchPlus, and avoiding data re-entry, could be one way to do that." Other Aspen products useful for process visualization or analysis include BatchCAD, a design program for continuous stirred-tank reactors, Aspen EBRS, for electronic batch-records management, and Aspen Process Recipe, for recipe documentation and data storage.At Eli Lilly (Indianapolis), associate engineering consultant Doug Watson uses Batches, a simulation program from Batch Process Technologies (BPT; West Lafayette, Ind.) to test the changes created by retrofits of new equipment or process flows. "A key part of this process is analyzing utilities, such as buffer solutions, clean-in-place capacities and the like, and ensuring that there is sufficient capacity," he says. The program does not provide strong visualization tools, but its numeric output is valuable for producing what-if analyses of design alternatives.Batches and its complementary program, BDist, for distillation work, follow the format of the ISA's S88 standard structure for batch process design, says BPT's president, Girish Joglekar. "S88 defines a modular approach for process design and recipe management, and if you follow it closely, you can start with very early-stage process design through to actual production," he says. The Batches program can be used either to look at one unit operation, or at the output of an entire production line. BPT has developed a library of process models, which can be used to stitch together a preliminary process design; the user can also develop new models. A database of physical properties is also available to evaluate process kinetics.Another simulator vendor, Intelligen, Inc. (Scotch Plains, N.J.) offers SuperPro 5.5, which was derived from research originally conducted at MIT's Biotechnology Center for biotech process design. The program has the advantage of integrating process design with environmental processes, so that an integrated production scheme can be developed, according to company president Dimitri Petrides. There software is used widely in both pharmaceutical manufacturing and engineering and construction, he says.Walk Through the ModelOnce a process flow diagram has been derived, it's usually time for a pharmaceutical company to bring in an engineering, procurement and construction (EPC) contractor. This is frequently the key step in successful collaboration, because there are major time savings to be won,or lost,in translating the process design into a constructed facility.However, it can help advance the project to bring in the EPC even before the process design work is complete, according to Kumar Gupta, a senior director at Process Facilities, Inc. (PFI; Boston), a company that was recently acquired by Parsons Corp. of Pasadena, Calif., and will now be known as Parsons Commercial Technology Group."Larger companies tend to want to do their own process design, while smaller ones will depend on us to some degree to collaborate on process design," he says. "In either case, our early involvement can result in a faster-to-market project." PFI has developed a collaborative work process called Solution One to formalize this collaboration. "Our requirement is that the kick-off meeting involve all stakeholders, including the R&D people as well as engineering," he says. "We get some pushback from the project managers sometimes, who believe that we are trying to go around them in their organization. But this is really the best way to proceed."Like practically all EPCs, PFI is a heavy user of engineering design and data management tools, including both purchased and in-house design simulators. "It's still remarkable how much design information you can cram into an Excel spreadsheet program," notes Gupta, in talking about the in-house simulation software.A key functionality of these systems is the ability to visualize both the process schematics, as part of generating the piping & instrumentation diagrams (P&IDs) that are a basic construction document, as well as for visualizing the as-built facility. "With the 3D design programs available now, you can perform simulated walk-throughs with the client, and they can decide whether the orientation of equipment and utilities is right for them," he says. PFI has done extensive work for designing and building R&D facilities as well as production facilities, and Gupta says that the visualization capabilities are important to both. "At the beginning of my career, some 30 years ago, the conventional practice was to build a scale model out of pieces of wood and sticks; this is so much better," he says.Gupta adds that an important time-saving step in the design-and-build process is to capture information critical to plant validation while the design work is going on. "There are cases where a plant has been built and needs to sit idle for more than a year because there is a problem in validating it," he says. "If you set up the design workflow properly, you can begin preliminary validation work even before the first shovel goes in the ground. You can cut months from the validation schedule if you do this right."Faster, Easier ValidationTime and money are on the minds of all engineering-design software firms as they pitch their products to both owner-operators and EPCs. Intergraph Inc. (Huntsville, Ala.), has commercialized its SmartPlant Engineering Framework, a software architecture into which its products, including the flagship PDS design program, fit. "We've done all the things necessary to meet CFR Part 11 compliance with software development, and that means that the design will comply with validation requirements even as it's being worked on," says Frank Joop, business development manager. Under FDA's Part 11 requirements, which are still being finalized, a software vendor has to audit and validate its own software development processes; at the same time, the user of the software must validate the program output as a step toward validating the as-built plant. A new capability of SmartPlant, says Joop, is the ability to store process designs as they are being revised,in essence, a "playback" feature that allows design changes to be reviewed retrospectively. "Pharmaceutical clients we've shown this to are very excited, because they see the validation value of this feature," says Joop.Ultimately, the collaborative features of Intergraph's and others' design tools result in a faster time-to-market process for the pharmaceutical producer. In the cases of blockbuster drugs, literally every day that can be cut from the pre-production phase can result in more long-term profit to the manufacturer. This collaboration increases the complexity of the project, but is a necessary step. As Schering-Plough's CEO, Fred Hassan, notes, "Success increasingly depends on an ability to create and sustain savvy partnerships in almost every area of our work."
Visualization software is helping to streamline R&D and allow researchers and manufacturing professionals to connect earlier in the drug development cycle. Shown here, an HIV-1 protease complex, viewed using DS Viewer Pro. Photo Courtesy of Accelrys