Erik Greb

Cognex 
 Enhanced display provides greater control


 Cognex (Natick, MA) offers new features to its “VisionView” operator display panel, which communicates with the company’s “In-Sight” and “DVT” vision systems. Engineers can now use the In-Sight system to choose vision-system parameters to display and modify on the factory floor. Through touch-screen controls, operators can use VisionView to change lot codes and change regions of interest. Operators do not need a computer to make these changes, which saves time during product changeover. Engineers can apply password protection to allow only authorized personnel to change critical processes.

An additional benefit of the enhancement is that it only exposes operators to the parts of the In-Sight software that they need to control the vision system, says Narayan Subramaniam, Cognex’s product manager for VisionView. Operators thus do not need extensive training to use the display. He adds that the new VisionView makes it easier to deploy an operator panel.

W.L. Gore and Associates
 Online interface facilitates fluid-assembly design


 W.L. Gore and Associates (Newark, DE) has introduced its “STA-PURE Bioprocess Configurator,” an online tool that allows users to design single-use fluid assemblies for biopharmaceutical manufacturing. The interface includes menus of components, including tubing, connectors, and peripherals, that users can drag and drop into a workspace to design an assembly. The application quickens the design process and helps clients communicate what they want to build. The tool thus allows clients to begin production quickly, according to Greg Tronto, business leader of single-use bioprocess components.

The STA-PURE tool includes built-in rules that do not allow users to design assemblies with parts that do not fit. Users can create nonstandard designs, however, Tronto explains. Components automatically snap in place in the correct orientation when users drag them around the drawing. The application allows clients to save their designs, which alerts Gore that a user might need assistance. It does not prompt users for personal information until they are ready to save or submit their design to Gore. 

Articles

PharmTech's monthly newsletter, Equipment & Processing Report, reviews the Editor's Picks for the October 2008 edition from Cognex and W.L. Gore and Associates.

October 2008 Editor's Picks: Products from Cognex and W.L. Gore and Associates

The pharmaceutical industry is a fairly old industry, and as such, the modern manufacturing facility really reflects an evolution—the aggregate of incremental changes. For example, the plant today is far more automated than its antecedents. It can be managed in part through software that didn't even exist when the industry was young.  

Illustration by M.McEvoy. Images: James Hardy, AtomicSupersonic, Photodisc (Getty Images) 

The software packages that have evolved include manufacturing execution systems (MES) and enterprise resource planning (ERP) systems. MES helps pharmaceutical companies monitor and control the plant floor. ERP systems help manage and monitor business processes. 

Integrating these new applications into a cohesive whole can bring a manufacturer great control, speed, and flexibility, but is a difficult project. Information technology (IT) standards, newly emerged tools, and planning, however, can make it easier to link the factory floor to the management suite to achieve great benefits. 

 The Instrumentation, Systems, and Automation Society (ISA) defines MES in its ISA-95 standard by providing data structures that represent the information that it manages (e.g., material, equipment, personnel, machine capability, and machine schedule). 

The manufacturing benefits of MES are manifold. The system automatically checks whether manufacturing equipment is operating within the correct parameters. It also verifies that components (e.g., containers) are appropriate for a particular production. Thus, it can reduce a site's number of material exceptions. Exceptions can be handled immediately, and deviations can be channeled into a corrective action/preventive action system. 

In conjunction with these checks, MES includes a process for electronic signatures and approval for each manufacturing activity. This function provides additional oversight of the production cycle and facilitates regulatory compliance. 

Manufacturing-data management also can be enhanced by MES. The system collects production data and creates electronic batch records that are available for analysis after production is complete. Electronic batch records enable review by exception, says Brian Leinbach, MES deployment lead for Wyeth Pharmaceuticals (Madison, NJ). MES's initial equipment and material checks reduce exceptions and, consequently, batch-record review time—often dramatically. Leinbach reports that MES helped one of Wyeth's sites reduce its cycle time from 36 h to 4 h, largely because it streamlined the record-review process. 

MES identifies processes that could be modified to improve efficiency, so it helps reduce manufacturing-cycle time. The process optimization that MES enables can yield labor efficiencies, improved compliance, process robustness, and repeatability.  

 ERP systems are likewise designed to collect, monitor, and store near-real-time data from various sources within a company and archive them in a single repository. Their goal is to improve business planning by providing easy access to current, detailed information. Most ERP systems store data for various functions (e.g., purchasing and supply-chain management) in a unified database. In other cases, a company will create an interface to allow its ERP system to access data in other systems. 

ERP systems can help companies streamline business processes and workflows. The systems also enable various departments in a company to share data easily and help improve project and inventory tracking, demand forecasting, and resource planning. 

If an ERP system replaces several smaller systems (e.g., supply-chain management and warehouse management), it reduces a company's software-maintenance requirements. When the ERP system establishes a single database for several departments, it can provide detailed reports easily.  

For an ERP system to provide the greatest advantages, a pharmaceutical manufacturer must integrate it with MES. Integrating the two systems helps companies perform global supply-chain planning by facilitating real-time monitoring of productivity, quality, and throughput. Integration also allows management to see the current location of inventory, work-in-progress, and raw materials. 

Another benefit for supply-chain planners is the ability to identify ingredient suppliers and contractors that could take part in a lean manufacturing process, according to Jim Sabogal, vice-president of industry solutions for life sciences at SAP (Newtown Square, PA). 

Integration also enables production orders to be sent to the plant floor—or multiple plant floors—quickly. Manufacturing personnel can thus fulfill orders sooner and reduce cycle time. 

Tight integration of MES and ERP systems provides accurate inventory counts to the enterprise level and also ensures that a company only picks released material for batch manufacturing. Integration prevents the site from "using batches that could be quarantined," Leinbach says. 

If the ERP system is integrated with MES and other systems, with a laboratory information management system (LIMS), for example, it can facilitate batch release, says Rolf Blumenthal, senior director of international consulting at Werum Software and Systems (Lüneburg, Lower Saxony, Germany). For example, the ERP system can collect the MES batch records for approval along with the inspection data from the LIMS system and present them together, thus providing improved visibility of information. 

If a company has unconnected information systems, collecting and collating data for document requests during inspections by the US Food and Drug Administration is a considerable effort, according to Herschel Kenney, senior director for IT planning and resource management at Purdue Pharma (Stamford, CT). MES–ERP integration speeds up this process by collecting the data in real time and allowing manufacturers to submit them to inspectors in minutes. 

MES–ERP system integration also has advantages for manufacturers even before they face inspections. MES and LIMS reduce the time needed for compliance activities. Because they automatically check equipment, materials, and production data, these systems, when properly integrated, make results available to the ERP system, which allows management to respond to exceptions or failures quickly. SAP's ERP system includes tools that ensure audit trails and electronic signatures, says Mandar Paralkar, one of the company's solution managers for life sciences. These functions help reduce the occurrence and effect of products manufactured outside specifications and enable the company to maintain regulatory compliance more easily. 

The right information infrastructure, tools, and applications are prerequisites for integrating MES and ERP systems. 

 Because manufacturing plants are not all built the same way, pharmaceutical companies need standard processes and definitions to choose the kind of information to communicate between the MES and the ERP system. ERP-system vendors point out that the ISA-95 and Manufacturing Enterprise Solutions Association (MESA) International standards provide a strong foundation for integrating enterprise and production systems (see Figure 1). For example, Sabogal says SAP uses ISA-95 and MESA to identify the key business processes, interfaces, and integration points essential for this integration. And SAP's software presents process orders to the production level in the ISA-95 standard. 

Figure 1: The manufacturing levels described in the Instrumentation, Systems, and Automation Society ISA-95 standard., Illustration by M.McEvoy. Images: James Hardy, AtomicSupersonic, Photodisc (Getty Images) 

Blumenthal says that Werum based its recently developed "PAS ECMI" software package on the ISA-95 standard. The product is designed to directly integrate SAP's ERP system with Werum's MES for certain defined business processes in the weighing and dispensing area. 

It's also important to standardize MES and ERP systems within an organization. "If you have one or a limited number of SAP instances, and they're all the same, then integrating MES and SAP can be simplified and the risk reduced" because only two applications (i.e., one MES and one ERP) are being integrated, says Richard Lemire, head of global production IT at Novartis (Basel). 

 Companies can simplify integration further by choosing a single format in which standardized MES and ERP systems communicate data within a messaging layer. A precedent has already been established, according to Kenney. "Right now it looks like XML is going to be the leading language for integrating packages," he says.  

XML provides a format to exchange information about items such as orders, materials, and the status of an operation. SAP software supports XML for "the customers who are ready to use cutting-edge technology," adds Paralkar. 

Novartis's harmonized MES and ERP systems use adapters that convert messages into XML so they can be exchanged, Lemire explains. He says that this solution is easy and takes only hours to execute. Similarly, Wyeth uses IBM's "MQSeries Integrator" application as an interface between its MES and ERP systems. The integrator converts XML messages into readable formats so they can be exchanged between the ERP system and MES. 

In addition to XML, which defines the general structure of data to be exchanged, manufacturers need a specific way to define data content. SAP developed the intermediate document (IDoc) structure to enable data interchange and distribution through electronic messages. 

Many companies now use Business to Manufacturing Markup Language (B2MML), which consists of XML schemas that implement the data models in the ISA-95 standard, to exchange data between their production and enterprise levels. When Genentech (San Francisco, CA) began integrating its MES and ERP systems, "SAP was publishing messages in the IDoc structure, and we had to convert them into the B2MML format" to communicate with the MES, says Govi Sridharan, senior automation engineer at Genentech. The conversion required Genentech to build custom integration. The widespread adoption of B2MML led SAP to provide B2MML content packages. 

 Establishing uniformity within the messaging layer also helps integrate a single ERP system with various MES systems. Genentech bought manufacturing facilities that used different MES systems from the one used at the company's other production plants. "We actually used the messaging layer for standardization," Sridharan says. The company gave the new plants the necessary touch points to publish data in a standardized XML format and introduced them to its common messaging layer. The strategy allowed Genentech to successfully integrate its ERP system with three different MES systems. 

 Middleware can enable production-level applications to view enterprise-level information. For example, business application programming interfaces (BAPIs) facilitate external access (e.g., by an MES) to business data in SAP's ERP system. BAPIs also enable data exchange between MES and ERP systems, says Paralkar.  

 Pharmaceutical manufacturers also should create clear workflows to assign responsibility for each part of the production process to their MES and ERP systems. Blumenthal says that when a company's business processes are well-known, tight integration is easy and systems can be deployed without customization. If a company does not use best-practice business processes, the software vendor must take time to understand these processes to adjust standard data migration exchange for each of them. 

Procedures such as documenting, measuring, and mitigating risk are performed in more than one IT system, notes Ruediger Dorn, managing director of the pharmaceutical industry at Microsoft (Redmond, WA). Microsoft's "Sharepoint"-based solutions can establish an infrastructure that provides uniform workflows to MES and ERP systems. This arrangement facilitates a continuous trail of control and allows companies to document a process, identify the employees who modified it, and prove the results. This information must ultimately be accessible to the ERP system, he explains. 

 SAP's "Manufacturing Integration and Intelligence" (MII) platform is a solution that allows users to bridge the gap between SAP's ERP system and plant-floor systems such as MES and LIMS. Andy Dé, SAP's senior director of solutions marketing in life sciences, says MII includes prebuilt adapters for the most common MES, LIMS, and quality systems. Once MII has been implemented, it extracts real-time data from the user's plant-floor and ERP systems and presents them within role-based dashboards. MII delivers analytics, reports, and alerts to improve decision-making and monitor performance. Firms such as Merck, Wyeth, Roche, and Novartis are using MII to integrate their MES and ERP systems. 

 Enterprise application integration (EAI) tools, particularly those that offer application-interface level EAI, use the process and data interfaces that the source and destination systems expose to extract and translate information between two or more systems. Commercial offerings include IBM's "WebSphere," Microsoft's "BizTalk Server," TIBCO's application, and Oracle's "BPEL Process Manager," says Alison Smith, research director at AMR Research (Boston). 

These EAI tools are much more sophisticated than MII, Smith says, because they're not specifically geared to SAP. Instead, they are designed for highly heterogeneous environments. The manufacturing industry is just starting to adopt these technologies, especially companies with an IT infrastructure complex enough to warrant a bus architecture that allows systems to exchange message-based information. 

EAI tools require a level of IT expertise and architecture awareness that typically isn't found in operations environments, says Smith. MII is not a plug-and-play solution, either, because users must have HTML programming skills to realize all of the tool's benefits. "None of these tools is easy to use," Smith says. "Any way you cut it, you don't get to do these integrations in a purely point-and-click way." 

 Blumenthal describes a way that Werum is working to facilitate MES–ERP system integration. MES and ERP systems are controlled by recipes, and integration entails synchronizing the systems' recipes on certain touch points. A master batch record (MBR) is an MES recipe that describes how to manufacture a given product. Werum's customers have asked it to provide "typical" MBRs to reduce their workload and help them adhere to best practices. 

Responding to demand, Werum is collaborating with its users to develop best-practice business-process descriptions. These descriptions are being transformed into reusable MBR parts and made available in libraries as typicals. The typicals will become part of Werum's MES and facilitate synchronization with SAP recipes, and thus integration with SAP's ERP system. 

 Various strategies and tools enable pharmaceutical companies to integrate their MES and ERP systems, although no current solution is ideal. Sabogal points out that a company must decide which of its IT systems is the system of record for regulatory purposes. Firms would be inclined to choose the system that could provide the relevant data the fastest during an inspection. 

Yet the required data might not be stored in one place. The MES contains batch records, detailed workflows, recipes, and other manufacturing-process information. An inspector would need this data, but would also need information about ingredients and quality-control inspections from the LIMS and supply-chain data from the ERP system. 

The ERP system should probably be the system of record because data about all of these elements ultimately flow to the enterprise level, advises Kenney. Though ERP systems do receive these data, such systems have traditionally focused on outcomes, planning, and timeliness of delivery. A thorough integration of the ERP system with MES and LIMS might be necessary for quality and compliance data to be available at the enterprise level. 

 The question of where work-in-progress (WIP) data should be maintained is also important for regulatory compliance. When MES and ERP systems are fully integrated, the enterprise view retrieves WIP data no matter where it is located and no matter how many places store it. Viewing WIP data at the enterprise level not only facilitates compliance, but also assists a company in its inventory and financial planning. 

But according to the MESA model, tracking and managing inventory, including WIP data, is MES's responsibility. WIP data need material-identification numbers for the ERP system to track them. Because MES identifies WIP data with its own rules, separate identification numbers in the ERP system could create confusion. 

On the other hand, maintaining WIP data at the production level is complicated if the manufacturing process takes place at several plants—particularly if the plants use different MES. This situation would require MES to be standardized. 

If a company's MES and ERP systems were integrated, then "all of the systems would be looking at the same inventory without having to worry about ownership," as Kenney points out. "The question of which package owns the inventory indicates that the integration is not where it could be." 

Several strategies and software applications help pharmaceutical companies integrate their manufacturing execution systems and enterprise resource planning systems.

Putting Together the Pieces

Software vendors argue that integrating manufacturing execution systems (MES) and enterprise resource planning (ERP) systems is a less daunting project now because the technology has advanced and users have become more sophisticated. "It's not a miracle anymore," says Rolf Blumenthal, senior director of international consulting at Werum Software and Systems (Lüneburg, Lower Saxony, Germany). For the most part, pharmaceutical companies that use the software generally agree.  

Still, some manufacturers wish the task were easier. Integrating these two systems "is still a lot of work" and "a custom job for each customer," says Herschel Kenney, senior director for information-technology (IT) planning and resource management at Purdue Pharma (Stamford, CT).  

Kenney and other users want a plug-and-play ability to integrate different software packages. The vendors are beginning to tackle this problem. SAP (Newtown Square, PA) seeks to provide solutions that enable integration so its manufacturing customers can harmonize their shop-floor and enterprise levels, according to Jim Sabogal, vice-president of industry solutions for life sciences at the company.  

SAP and Werum have collaborated to simplify the integration of their products, and the companies say this strategy will continue. Werum's "PASECMI" solution is a result of the collaboration with SAP. The solution combines a fixed selection of modules that support well defined business processes in the weighing and dispensing area. It provides out-of-the-box integration with SAP, Bluementhal says.    

SAP, Werum, and Tata Consultancy Services jointly built a Perfect Plant Center of Excellence at SAP's headquarters. The center allows pharmaceutical customers to experience the companies' integration solutions firsthand before adopting them.  

Microsoft (Redmond, WA), too, collaborates with MES vendors such as Aspentech, Emerson, and Siemens, adds Ruediger Dorn, the company's managing director of the pharmaceutical industry.  

Users would also like to see MESes, ERP systems, and interfaces that require little maintenance. For example, updates should be required less frequently, and should not involve extensive retesting of functionality, Kenney says. Systems should also archive data efficiently and let users perform backup while the systems are running.  

When a pharmaceutical company performs IT maintenance, it must submit change-control, risk-analysis, and technical-assessment documents for regulatory approval. Designing MES software according to good software engineering practices and following software-development life cycle practices would reduce maintenance requirements, says José Matos, manufacturing-systems and process automation manager at Bristol-Myers Squibb (New York).  

The fact that integration still involves writing custom code means that system upgrades require new coding and extensive testing, observes Govi Sridharan, senior automation engineer at Genentech (San Francisco, CA). A plug-and-play integration solution could reduce maintenance.        

Reducing the cost of integration is another user demand. If vendors follow good software engineering practices and open architectural systems standards, it will minimize the cost of ERP–MES commissioning and validation, according to Matos. Applications that follow the service-oriented architecture design can help lower intergration costs, Kenney says, as would plug-and-play (rather than custom) integration.  

Sridharan would also like to see MES and ERP systems send and receive data in a standard, Business to Manufacturing Markup Language (B2MML)-compliant format. Nonstandard formats require companies to write and validate custom code to exchange data between systems. Using the B2MML-compliant format would "drastically reduce" the cost of integration because "the integration layer just becomes a transportation layer without any modification of data," Sridharan explains.  

Companies also express interest in using MES to share quality-assurance (QA) responsibilities among manufacturing sites. Being able to allow a central team to perform QA checks of products made at another plant and, conceivably, initiate corrective action remotely is a distinct advantage, Kenney says. This arrangement could promote best practices and complete investigations quickly. Users would like to achieve this functionality without the need for expensive custom integration.  

Companies already use MES to review batch records by exception. Integrating MES with an ERP system allows events to be managed and recorded online. Once a firm had this capability, it could create a batch-record review center of excellence to examine data from multiple global sites. The center of excellence could save time because the global reviewers would become proficient. It would also save money because best practices would naturally be disseminated throughout the global organization, says Kenney.  

"To the extent that that batch-record review occurs online, it doesn't matter where the reviewer sits," Kenney says. Centralized review and online reporting to regulators could improve the speed and quality of reviews and allow a company to optimize its record-review function, Kenney adds.     

Pharmaceutical companies want software vendors to make integrating manufacturing execution systems and enterprise resource planning systems easier.

Integration the Easy Way

The US Food and Drug Administration requires that all equipment used to manufacture pharmaceuticals be qualified. Put simply, qualification demonstrates that equipment is what it is purported to be and does what it is supposed to do. Installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ) are the three steps of equipment qualification. 

Although most drug companies either have a knowledgeable qualification group or rely on outside experts to perform these qualifications, some manufacturers make common mistakes that thwart their qualification projects. These mistakes often result in qualification failure, which costs companies time, money, and effort.

The most common, and the most consequential, mistake is a lack of planning. The pressures of commercial manufacturing can lead many drugmakers to spend little time planning for qualification projects. Some believe that extended planning is inefficient; their goal is to release the equipment for production quickly. But insufficient planning-not extended planning-is inefficient, according to Jeff Hall, consultant at MHP Consultants (Roswell, GA). “With poor project planning, typically the project-completion date shifts incrementally because of delays in the project or poor oversight,” he says. Poor planning can also result in failed validation.

Even when manufacturers take time to plan qualification projects, they sometimes ignore important considerations. Companies often fail to take a science- or risk-based approach, based on product and process knowledge, to define the extent of qualification, says Steve Wisniewski, director of compliance at Integrated Project Services (Lafayette Hill, PA). 

 agrees that risk analysis is essential to the planning process for an IQ, OQ, or PQ project. Risk analysis identifies the critical and noncritical work to be done and helps companies focus on the appropriate elements of the qualification project. Validation should address the critical areas, and commissioning should address the noncritical.

Because it identifies the factors that have a direct effect on product or process quality, risk assessment can also reduce the number of systems requiring qualification and robust commissioning, Wisniewski says.

During the qualification-planning process, manufacturers sometimes do not consult all of the employees who will be responsible for using, maintaining, or approving the equipment. This oversight leads to inadequate plans that delay the completion of qualification projects or result in failure to meet requirements. “A successfully executed qualification is difficult to obtain without a good core knowledge of the equipment and its operation,” Hall says.

Another widespread mistake is the failure to apply sound project-management principles to commissioning and qualification projects, explains Wisniewski. Companies should define commissioning and qualification activities and clarify who will be responsible for each one. In addition, manufacturers should map the documentation control that the qualification project requires, says Wisniewski.

Qualification plans must be monitored, says Hall. Companies should use a project-plan approach to assign milestones to each test completion. Also, management should be notified of successful test completions and delays or problems that the testing team encounters. “Regularly scheduled updates on the progress of the qualification are ideal,” Hall remarks.

By taking several steps, pharmaceutical manufacturers can improve their IQ, OQ, and PQ projects. For example, Hall points out that the intent of equipment and instrument qualification is given in FDA’s 

Guideline on General Principles of Process Validation

 “The intent of the qualification process must be met with every qualification, no matter the type of equipment or instrument,” he says.

Regulators and manufacturers use different terms to discuss IQ, OQ, and PQ, and this lack of uniformity can cause confusion. Manufacturers can decrease the confusion by including detailed definitions within their sites’ qualification plans or protocols, Hall remarks.

Finally, drugmakers should allow sufficient time for qualification projects, says Pluta. After a company budgets adequate time to plan the qualification and subsequent development work is complete, IQ, OQ, and PQ should begin. Companies need to devote as much time as necessary to understanding their systems fully before such programs begin.

Collaboration, prioritization, planning, oversight, and clarity of purpose can greatly improve pharmaceutical-equipment qualification projects. These factors can save drugmakers a lot of time, sweat, and money.
 

Qualification demonstrates that equipment is what it is purported to be and does what it is supposed to do. Installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ) are the three steps of equipment qualification.

Qualification Pitfalls and How to Avoid Them

LiquaJet 
 Technology mills resistant materials


 LiquaJet (Moorestown, NJ), a new company created by the Jet Pulverizer Company (Moorestown), offers jet-milling services based on a new, proprietary technology. The technology uses high-purity compressed liquid nitrogen rather than compressed gas. The compressed liquid nitrogen expands after entering the jet-milling chamber and provides greater pressure and force than compressed gas does.

The process mills materials that were previously ungrindable. For example, the technology grinds plastic and polymers that could previously be reduced to 100–200 µm to less than 30 µm, according to the company.

The LiquaJet technology contains no moving parts, prevents contamination, and does not create additional heat. The technology minimizes material loss and produces high yields that comply with good manufacturing practices. The company is inspected by the US Food and Drug Administration.

Yokogawa Corporation of America 
 Production-control system has new features


 Yokogawa Corporation of America (Newnan, GA) has added pharmaceutical batch-control capabilities to its “Centum VP” integrated production-control system. New features include recipe-management and process-management functions in addition to the application’s unit-supervision and process-control tools.

The Centum VP software now provides a configurable unit faceplate that lets users monitor and execute batches through an interface. The application also features standard displays for product overview, product control, and unit control for recipe and product selection. The displays offer automatic, current documentation of the batch logic.

In addition, the software separates recipe data from equipment data and provides unit-based exception handling. The latter function allows batch engineers to create modular procedures for main production activities, engineer exception handling through unit monitors, and interrupt processing if necessary. Thus, automation engineers can execute failure-handling logic one time, rather than during each phase of production.

PharmTech's monthly newsletter, Equipment & Processing Report, reviews the Editor's Picks for the September 2008 edition from LiquaJet and Yokogawa.

September 2008 Editor's Picks: Products from LiquaJet and Yokogawa

Nanoparticles are the center of many drug-delivery specialists' attention because they can form the basis of mechanisms that provide targeted and controlled drug delivery. Because nanoparticles also enhance drug stability and reduce immunogenicity, they provide a particularly advantageous solution for biological drugs. But they are not the only option on the table. 

One common approach to delivering protein drugs is to attach polyethylene glycol (PEG) molecules to their amine groups. This process is called PEGylation. Anjan Nan, research assistant professor at the University of Maryland School of Pharmacy (Baltimore, MD), says that this technique has several advantages. 

First, PEGylation reduces the protein's net amount of available amine groups, thus decreasing its net charge. "As a result, the whole formulation is less immunogenic because the body doesn't react to that excessive charge," Nan explains. "This is an easy and efficient strategy to make immunogenic molecules nonimmunogenic." 

The hydrophilic nature of PEG molecules also reduces immunogenicity. Once a PEG molecule is bound to a protein, it attracts water molecules. This hydration reduces the likelihood that the body's immune system will recognize the molecule as a foreign object, Nan says. 

PEGylation makes proteins more stable, too. In general, PEGylation reduces the plasma-clearance rate by decreasing the metabolic degradation and receptor-mediated uptake of the protein from the systemic circulation. Conjugating PEG to proteins results in lower protein aggregation, reduced protein adsorption, and protects against antigenic and immunogenic epitopes. 

Nan adds that PEGylation can also provide targeted delivery of protein drugs because it increases their molecular size. Big molecules move toward sites such as tumors and inflammations because those areas have leaky vasculature. "You can take advantage of such a macromolecular delivery system to selectively deliver to the site of action," says Nan. 

Dr. Frank Sorgi, vice-president of research and development at DPT (San Antonio, TX), acknowledges PEGylation's benefits, but counters that PEG molecules can also prevent the drug from being taken up by the body. As is the case with other drug-delivery strategies, PEGylation requires scientists to find a trigger that cleaves the protecting or targeting molecules from the drug at the site of absorption. Current techniques may include using pH, heat, light, or the administration of other components. "You can see just how complex this gets because you need to build up and then tear down the molecular complex to make it biologically active," remarks Sorgi. 

Microparticle-based systems such as MannKind's (Valencia, CA) "Technosphere" technology employ a different drug-delivery strategy for biologicals. The technology involves loading drugs onto fumaryl diketopiperazine (FDKP) microparticles for pulmonary delivery. Upon inhalation, the Technosphere particles travel to the deep lung, where they dissolve immediately. Technosphere particles do not play an active role in drug absorption, explains Peter Richardson, MannKind's chief scientific officer. Instead, the FDKP and the drug are absorbed by natural mechanisms. The FDKP is excreted unmetabolized, primarily in the urine, and the drug enters the systemic circulation.  

Technosphere technology could enable the pulmonary administration of therapeutics currently administered by injection. According to Richardson, the technique offers several advantages over other pulmonary drug-delivery systems. For example, drugs inhaled as Technosphere formulations have pharmacokinetic profiles that result from rapid systemic absorption from the lung directly into the arterial circulation. Technosphere delivery also bypasses first-pass metabolism. 

MannKind's research has demonstrated that insulin can be stabilized in the monomer form when formulated with Technosphere particles. The technology thus "has the potential to allow the development of drug candidates that would not otherwise be feasible," says Richardson. 

In addition, the technology is compatible with drugs that have various physicochemical characteristics. "Drugs that are anionic, cationic, hydrophobic, hydrophilic, and those with high molecular weight have all been delivered using Technosphere technology in preclinical models," Richardson says. In addition, the technology has been used successfully to prepare formulations of drugs with molecular weights of 500–140,000 Da. 

The pharmaceutical industry's interest in biological drugs is growing, partly because of these therapies' promise for improving treatment for patients, and partly because they could boost companies' dwindling pipelines. Protein-based drugs, and their interactions inside the body, are complex, but science's understanding of them is growing. Even now, drugmakers have various effective drug-delivery options to choose from. Researchers such as Nan and companies such as MannKind give reason for optimism that the industry can overcome the challenges that biological therapies pose.

Small Wonder: Nanoparticle Strategies for Biological Drugs

Although the spotlight is now on nanoparticulate delivery for biologicals, other strategies have proven successful.