The XYZ 3000 by BioDot Inc. (Irvine, CA) is a batch dispensing platform with BioJet Quanti 3000 and AirJet Quanti 3000 dispensers.

The IVD market is relatively small, constituting less than 5% of total healthcare spending. It has, however, experienced significant growth over the past 30 years, despite a recent slowdown attributable to maturation and consolidation. Now, with IVDs as with any other medical device, quality is a major product component—something a regulatory authority expects to see and a customer pays to get.

Medical device manufacturers must meet standards for quality systems and for the performance of specific classes of devices. The establishment of quality systems in IVD production facilities has transformed the quality function from weeding out bad manufactured parts to preventing bad parts being produced in the first place. Total quality systems have imposed more-stringent requirements on all elements of the IVD supply chain, from raw-materials suppliers to service providers, and suppliers of manufacturing equipment to the industry.

The trend toward the establishment of total quality systems has imposed the need for true process control. IVD manufacturers must monitor quality at all stages of the manufacturing process, in order to ensure good product consistency and quality. Collateral benefits to this include possible cost reductions and reduced in-process and finished-product scrap rates.

Most IVD devices are complex systems, relying on the interaction of biological, chemical, and physical processes for proper function. But key components of these systems are subject to variability caused by a number of things. It is crucial that the manufacturer understand both the potential sources of lot-to-lot or within-lot variation in the raw materials and components being integrated into the final product and the effect those variations could have on performance.

In addition, all incoming raw materials and components should be subjected to thorough and complete quality control (QC). Vendors often can be an important source of information in establishing appropriate raw-material and component specifications and incoming QC criteria.

In many instances, QC of incoming components involves functional testing, and therefore destroys the component. The cost of testing can quickly become an issue. The manufacturer must strike a balance between early detection of problems and superfluous testing of noncritical parameters. Hence the need for clear criteria, established whenever possible with the assistance of the suppliers of critical components.

Treating the vendor relationship as a partnership improves the chances of resolving issues in which clear identification of the core problem is difficult. For example, in lateral-flow devices, where critical reagent and component performance is often assessed in the context of finished-product performance, thorough and elaborate detective work sometimes is necessary to establish the cause of a performance problem. The vendor's help can be crucial in finding and correcting the defect.

Automation for Better Process Control

These syringe pumps by Hamilton Co. (Reno, NV) are available in several configurations designed for the optimization of specific fluid-handling applications.

The assessment of process and product quality for many IVDs depends on costly sampling and destructive testing of value-added parts. The cost of manufacturing them can be reduced if process- or component-related issues are identified early, if out-of-specification parts are removed early in the process, and if process data are gathered and assessed to prevent further generation of bad parts. One way to satisfy these conditions is by automating critical processing and process-monitoring functions.

Companies in the IVD industry are increasingly automating key processes. In some applications, continuous processing is becoming more prevalent. However, many IVD manufacturers still depend on batch or semibatch processing with a large element of manual work. They largely rely on equipment and process validation, training and supervision of employees, in-process verification of equipment and operator performance, and in-process sampling to ensure the quality of the product. If these manufacturers used continuous or automated processes, they could implement a wide variety of better process controls and product assessment safeguards that essentially cannot be used with manual processes. Nevertheless, manual batch processing remains the norm in many segments of the IVD manufacturing industry. Why?

The reluctance to introduce continuous automated processes has been based mainly on cost. In-line equipment involves greater capital outlay than batch equipment, so production volumes have to be large enough to justify the increased entry cost.

Also, historical process development and component selection decisions play a role. Many IVD manufacturing processes were developed solely with batch processing in mind. As a result, making a transition to continuous or automated processing can be difficult. Examples include processes that require long incubation times, curing of components, or long lyophilization cycles. Conversion difficulties can be compounded by development choices. Perhaps materials that have poor tensile strength or are not available in roll form have been selected for the product.

The inertia that many years of established practice has generated, along with the sometimes daunting challenge of revalidating processes and products, can stand as a serious obstacle to converting to automated or continuous processing. To justify the switch, the manufacturer must see that the automated process will enable the more efficient production of an equivalent or better product.

Automation can help most in:

• Minimizing cost.
• Minimizing variation in processed components.
• Detecting component variation as early as possible in the process.
• Identifying substandard parts and enabling their removal from the processing line.
• Monitoring processes in order to generate data that can be used to improve them.

As suggested earlier, the first consideration for an IVD manufacturer contemplating an automated line often is the cost of capital equipment measured against throughput. Decision making can stumble at this first hurdle. Capital equipment for automated processes costs significantly more than equipment for batch processing. However, throughput can be much greater with automation, and labor requirements considerably reduced. Also to be considered are associated improvements in process efficiency, scrap rates, and process monitoring and control. Once automated equipment is in place, products of consistent high quality can be manufactured at relatively low cost.

Automated Manufacturing Steps

Several basic IVD manufacturing steps lend themselves to automation and its benefits: dispensing and drying, lamination, cutting, and assembly and packaging.

Dispensing and Drying. Fluids may be dispensed to form lines or dots for a lateral-flow device, a biosensor, or a diagnostic array. Whatever the application, effective, consistent, verifiable, and validatable dispensing and drying processes are key to the device's proper functioning. The entire dispensing system—the fluid being dispensed, the matrix onto which it is dispensed, and the dispenser itself—must be considered.

Careful optimization and validation of process parameters are central to effective high-yield dispensing. Additionally, ongoing verification of these parameters, and of operator performance, is critical for obtaining consistent product. Monitoring batch dispensing processes for failures tends to be left to operators, who generally must make subjective decisions. A break in a line or the absence of a dot where one is expected can often be detected by a vigilant operator; on the other hand, consistent determination of line quality, volume dispensed, or drop placement is beyond the ability of most operators measuring by eye. Using automation for the assessment of parameters such as these is the only way to really assure consistency. Thus, camera systems coupled to analytical software and real-time statistical process control (SPC) packages are used in continuous dispensing operations. These allow for continuous objective analysis of dispense quality, as well as real-time bad-part identification and feedback to operators and process planners.

Drying is a critical process in the manufacture of many IVDs. Batch drying methods, however, provide great opportunities for product variation. Diligent validation and maintenance of batch ovens and lyophilizers is necessary to ensure product consistency. Variation in moisture loading, feed-air condition, air transport within the system, or temperature within the chamber can lead to inconsistency in dried product quality.

The use of continuous, or in-line, drying methods instead affords greater control of the drying process. It also allows real-time monitoring of the dryness of a matrix on a per-unit-length basis, ensuring that every unit length of product undergoes essentially the same drying process as the preceding unit length. Again, real-time feedback can be used to identify out-of-specification parts or process parameters. Operators and planners then can act promptly to remedy a failure mode.

Lamination. Manual lamination operations tend to require extremely high labor input and can easily become a bottleneck in the manufacturing process. The capacity for operator error is also high. Many lamination operations can readily be automated, however. In addition to vastly speeding the process, automation facilitates the performance of quality assessment. Sensing systems can be employed to ensure the correct orientation and placement of parts.

Cutting. In many automated continuous or in-line operations, the first opportunity to remove bad parts from the system comes at the cutting stage. Out-of-specification components that have been identified and marked in an earlier dispensing or drying stage can now be detected by sensors and removed before they become incorporated into assembled or packaged products. Their timely elimination reduces the potential cost of the error considerably. Again, using efficient automated sensing and rejection removes much of the risk of operator error from the process. A variety of methods for culling bad parts can be incorporated into automated cutting systems.

Assembly and Packaging. Labor requirements tend to be high in manual assembly and packaging operations. Manual processes demand capable workers, good training, thorough process validation, and constant vigilance. Here again, automation can vastly reduce the dependence on labor and the attendant prospect of manual error. Automating assembly and packaging of certain products under certain process conditions can, however, require custom system design and significant investment. Modular systems are available that can be tailored to the device, mitigating the expense somewhat. In these processes, too, sensing and camera systems coupled with SPC can be used for effective monitoring and control.

Planning for Automation

Deltron Precision (Bethel, CT) recently introduced compact leadscrew positioners with a height of 1.25 in. and a width of 1.38 in.

An IVD manufacturer deciding to implement any form of automation clearly must take into consideration a number of critical issues and should undertake some preparation. Like the component suppliers mentioned earlier, the equipment vendor can be a useful partner in the mission to create a product of high quality. The earlier in the system development process the equipment vendor gets involved, the more that vendor can help guide the manufacturer through product design traps that can hamper easy entry into automation.

Many of the equipment suppliers listed in this section of the buyers guide have years of experience in dealing with design issues and offer a bank of knowledge on which the IVD manufacturer should be ready to draw. They back their equipment with technical and scientific expertise as well as equipment-specific advice. Knowledgeable vendors can facilitate the discussion among the manufacturer's scientists, engineers, technicians, and marketing and sales personnel with the object of ensuring that manufacturing processes and equipment are installed that will produce good product cost-effectively and reliably on schedule.

The degree of diligence applied in choosing a manufacturing equipment vendor can mean the difference between the success and failure of a manufacturing project. Likewise, the care taken in defining the scope of the project initially can determine the ability of a machine to live up to expectations when installed. This task encompasses critical process, component, and product parameters such as component dimensions, tolerances, processing and handling conditions, and targeted throughput. Specifications should be defined and documented scrupulously during the planning phase. Small changes in component or product design can lead to large changes in machine performance.

Finally, in selecting a supplier of equipment or product components, the IVD manufacturer should make sure that the vendor can and will provide ongoing support. This is an especially important consideration in connection with providers of manufacturing equipment. Mechanical systems are always subject to failure, for myriad reasons. Any equipment can run smoothly immediately after arrival on the factory floor. The measure of a good automation company—as of any equipment supplier—is how well the machinery works in a manufacturing environment after operating for a while, and how well it is supported by the supplier when problems arise, as they invariably do, during a heavy production schedule.

In today's market environment, as regulatory requirements increase and profit margins become ever tighter, the margin for error is becoming smaller and smaller for the IVD product manufacturer. This is true at all levels of the IVD industry supply chain. The adoption of well-chosen automated manufacturing equipment to increase product quality while reducing production cost is a strategy for success that has good potential. The selection of suppliers that are willing to work with their customers to ensure their success is solid insurance. The forward-looking IVD manufacturer that wants to survive and grow in this business climate must choose partners, not just suppliers.

Brendan O'Farrell, BioDot Inc. (Irvine, CA)

Photos Courtesy Biodot Inc., Hamilton Co., Deltron Precision

Copyright ©2002 IVD Technology