Medical Device Link.

Originally Published IVDT September 2002

PROCESSING TECHNOLOGIES

Advances in packaging technology go hand-in-hand with market growth and new chemistry developments.

Ray Johnson

Continual advancements in IVD chemistries and technologies are enabling faster and more-precise diagnostic analysis, at higher volumes. In the background are equally impressive developments in IVD packaging automation that have been critical for delivering the new chemistries to market. Even established IVD products are benefiting from packaging technology advances as market forces drive volumes up and prices down. Recent improvements in IVD packaging are affecting diagnostic devices as well, and facilitating continued market growth.

The IVD industry originally concentrated on developing chemistries and methodologies for detecting more and more medical conditions. But as it has matured, selling and distributing existing devices in a highly competitive marketplace has become a focus of almost equal importance. Packaging has always been a secondary concern, even though its importance in protecting product was well understood. (From the beginning, most IVDs were packaged in high-moisture-barrier foil laminate pouches.)

Figure 1. A diagnostic device being contract packaged in a dry room, or cleanroom, facility.

Until recently, manual labor or semiautomatic equipment was most commonly used to package IVDs (see Figure 1). Only the highest-volume blood glucose, pregnancy (HCG), and similar tests were packaged by automated systems. After a packaging material and process became established for a product, seldom was consideration given to changing them.

The modest FDA requirements for IVD packaging, as compared with food and drug packaging, supported this "if it isn't broken, don't fix it" attitude. IVDs are not ingested. An improperly packaged IVD device would never directly cause an illness or death. Still, mispackaging an IVD can easily lead to an incorrect diagnosis and, as a result, serious health implications for the consumer.

Forces Driving Packaging Automation

IVD packaging has been changing dramatically lately. As a result of FDA finding good manufacturing practices (GMPs) wanting at a few large IVD manufacturers, the agency is focusing more than ever on the diagnostic industry. It now requires meeting higher packaging standards and adhering strictly to GMPs. The need to provide 100% process validation makes continued use of manual and semiautomatic packaging methods, and even older automated systems, problematic. Only advanced packaging automation technology can provide full validation.

Steady growth in sales of established high-volume IVD products is driving the practical need for very-high-speed automated packaging systems. Products with emerging high-volume demand now also are being packaged on automated lines instead of by their former manual and semiautomatic methods. The next section of this article discusses this trend.

Finally, many novel IVD chemistries being developed are especially sensitive to external factors such as humidity, atmospheric gases, and bacterial contamination. IVD manufacturers must utilize biocidal sprays, induced gases, vacuum packaging, and other techniques to neutralize these factors, which can only be accomplished efficiently through advanced automated packaging technology. This article also surveys advances in environmental control in some detail.

Volume Considerations

The largest manufacturers of high-volume IVDs such as HCG tests and blood glucose monitors have relied on packaging automation for years, being driven to the technology not just by the volume of market demand but also by competitive pressures to continually reduce product cost and increase margins. The machines they once used could package 100–200 IVDs per minute, for a maximum of 6 million units a month on a three-shift basis. A manufacturer might have needed 10 or 20 machines to produce and package the required volumes, even at those speeds. Each machine in turn required three or four operators per shift to run it and to handle material input and output. A production line thus could easily employ up to 100 people in what was considered a fully automated operation.

Because packaging efficiency was not seen as a competitive business advantage, companies long accepted this high labor requirement. Then their volume products became commodities. Subsequent pressures to lower shelf costs and at least maintain margins have created a demand for packaging efficiencies achievable only through higher levels of automation.

Integrated Production Lines. The current trend for high-volume products is toward fully integrated high-speed processing and packaging. New developments in automation technology enable manufacturers to produce up to 2000 IVDs per minute with only one or two integrated packaging lines rather than the 10 to 20 machines used typically. Because of the high level of automation, three or four workers per shift are sufficient to operate these lines. They primarily oversee material handling. Products are no longer input by hand, but instead are automatically processed and fed to the packaging machine at correspondingly high speeds.

Such highly automated packaging machines are designed to run continuously to eliminate the inefficiency of downtime. For example, automatic web-splicing of one roll of packaging material into the next eliminates the need for the machine to be slowed or stopped for an operator to load a new roll. The high volume of pouched IVDs produced by modern automated packaging lines is too much for operators to load manually into cartons; instead, the pouching machines must be linked directly to high-speed automated cartoners. Cartoned products are then fed to automatic case cartoners and then to automatic palletizers to be readied for final shipment.

High-output packaging lines are expensive. A complete line that processes 2000 devices per minute can cost as much as $2 million. But high-volume IVD producers will find that this investment in automation has a payback of about two years calculated on the basis of labor savings, reduction of waste, and efficiencies related to overhead costs. When the 20-year life expectancy of the line is factored in, the price tag is easily justified.

Quick-Changeover Lines. Packaging automation technology is not only for the very-high-volume or superrich IVD manufacturer. Many other companies need latest-generation packaging equipment either because their production volumes are rapidly increasing or because they make a broad range of products.

Worldwide demand for diagnostics for cholesterol, ovulation, H. pylori, blood alcohol, drugs of abuse, strep, influenza, and other targets of interest besides blood glucose and HCG is rapidly growing. These will require a high level of packaging automation. Full-line manufacturers package many of these tests under one roof.

But manufacturing multiple products in one facility makes production forecasting and planning complicated. Market demands are often hard to predict. For example, the flu test was recently in high demand following the anthrax scare because of the similarities in symptoms between the diseases. Also, strep test use fluctuates seasonally and depending on the strength of the bacterial strains. This unpredictability, along with the growth in demand for so many IVDs, has made it difficult for smaller manufacturers to commit to dedicated automated packaging lines as the high-volume producers have done.

Figure 2. A 4SS pouching machine by Doyen Medipharm in operation.

Fortunately, rapid-changeover packaging technology has become available. So-called toolless-changeover machinery that allows manufacturers to clear out a production line and change to different packaging materials and package dimensions in less than 20 minutes has been designed with the IVD industry in mind (see Figure 2). Although system speeds are limited to about 400–500 packages per minute, this technology enables IVD makers to package ovulation diagnostics in the morning and pregnancy tests in the afternoon without significant downtime.

This high level of flexibility allows medium-volume manufacturers to justify installing fully automated packaging machinery. The payback is from the reduced dependence on labor, reduced downtime, and increased packaging consistency and quality that comes with automation. With rapid-changeover packaging machines costing from $200,000 to $400,000, multiple-product manufacturers will see their investment returned in less than two years.

Sophisticated IVD Packaging

An IVD package is a complicated, self-contained system. It begins with the primary packaging material, typically a foil substrate with film laminates. The foil gauge and laminates are chosen carefully to ensure the optimal combination of package strength, ease of opening, moisture and air barrier properties, and production cost. Internal materials must not react chemically with the enclosed device or abrade it as a result of the shaking experienced during shipping. And materials for the outer package must be able to be printed or labeled and should satisfy marketing requirements for appearance.

After material selection comes package design. Decisions regarding package dimensions, seal widths, seal strength, easy-opening features such as thumb notches or tear slits, tamper evidence, and printed information are made for the benefit of the end-user. More importantly, the design must satisfy the functional requirement for maintaining hermetic seal integrity over time and long shipping distances. A package's design must also take into account the operational requirements of advanced packaging technology; for example, packages that can be small if filled manually commonly must be enlarged to accommodate high-speed automation.

To these material and package design requirements must be added the needs engendered by sophisticated new IVD chemistries. When the removal of air or moisture or the addition of gases or desiccant devices becomes necessary, the complexity of the packaging system becomes quite apparent.

The In-Package Environment. Emerging diagnostic devices include those that may be genetically engineered, give results 10 times more precise than before, or have a three-year shelf life—and complete test systems are being developed that reside on a strip, a chip, or a plate. With this increasing sophistication comes greater sensitivity to environmental factors such as humidity, particulate, bacteria, and air or atmospheric gases. IVD manufacturers must be able to precisely control these external elements, and remove air and humidity to degrees not previously thought possible. And sometimes they must introduce precise amounts of biocidal spray, inert gas, or other material into the package space. This can be accomplished only as an integral step in an automated packaging process.

To try to achieve standard IVD packaging requirements manually or with semiautomatic equipment is challenging; to satisfy the special requirements of new IVD chemistries by these methods is essentially impossible. Not only would the attempt add labor and exorbitant cost, but the accuracy, consistency, and quality required by the advanced devices would be out of reach. The best solution is automation.

A 4SS pouching machine by Doyen Medipharm Inc. (Lakeland, FL) packaging a high-profile IVD device. The white cassette is shown being automatically infed to the machine.

An in-line IVD packaging process that forms a package, loads a product, removes all the air, injects a precise dose of specially mixed gas, adds a desiccant, and then seals the package closed, all in a controlled environment of less than 3% relative humidity, is not so uncommon anymore. One company recently developed a diagnostic device that required vacuum packaging to a level of 29 in. Hg. This near-absolute vacuum pulled the foil so tightly to the enclosed product that printing on the device could be read through the package. This extreme level of environmental control could be achieved only through the use of sophisticated packaging automation technology.

Longer Shelf Life. IVD product shelf life is a key factor in competitiveness and profitability. If one company has a pregnancy test kit offering 12 months of substantiated shelf life and another's kit is proven to maintain a shelf life for 36 months, nearly any distribution channel—government, professional, or retail—is going to favor the product with the longer shelf life. Long shelf life is a significant advantage because it reduces the risk of product return due to expiration. This is a major cost that both IVD manufacturers and distributors want to avoid. Extended shelf life also reduces the chance of product failure due to aging. All IVD manufacturers closely monitor product performance because failure not only affects consumer perception but can also lead to product liability claims.

Three things can contribute to increasing IVD product shelf life: improving its chemistry, upgrading the package's material barrier to moisture vapor or air, and enclosing desiccants in the package. None of the above is a simple or inexpensive solution.

Although improving device chemistry sounds desirable, many companies hesitate to alter an already proven technology. Development is expensive, and a new chemistry would require additional functional, market, and FDA testing. Besides, to try to optimize an already fully developed product merely for shelf life would be difficult and could jeopardize other product features such as accuracy and speed. Few companies, therefore, are willing to invest in such an effort.

Changing barrier materials used in packaging can be a way to improve shelf life in cases in which only moderate protection against infiltration by moisture vapor or air was originally chosen. However, FDA requires additional extended stability testing of the product packaged in the new material, which also means potential piles of paperwork. Moreover, the cost of either increasing foil thickness or changing laminate structures to increase shelf life is often prohibitive relative to the benefit gained. It is not uncommon for IVD packaging-material cost to exceed the device cost.

Many IVD manufacturers have long had no other choice than to add desiccants to packages in order to ensure product effectiveness and maximize shelf life. Simply packaging their highly sensitive devices in a low-humidity environment would provide insufficient protection. Adding a desiccant tape, pouch, or canister to a package adds cost that rises proportionally with the level of desiccation provided. Labor requirements increase when the desiccant has to be manually loaded. Or the package may have to be larger to accommodate the extra component. Another concern has been whether the consumer would confuse the desiccant with the device. Field reports suggest that some naïve consumers throw away the device and try to use the desiccant for diagnosis.

New Desiccant Solutions. Today, packaging automation facilitates high-speed desiccation solutions that help manufacturers enhance product shelf life and performance much more economically than was previously possible. One approach, already noted, is the virtually complete elimination of air through vacuum packaging. Another method is the automatic placement of desiccant hot-melt glues in a fixed position on the interior of a package so as not to come in contact with the enclosed IVD. Special sealed compartments can be formed within a pouch, with venting holes for moisture transfer from the main IVD compartment being the only connection between the desiccant hot melt and the device. These approaches require accuracies in dispensing and package sealing that can be achieved only with sophisticated automated packaging machines (see Figure 3).

One especially significant development in product desiccation has been the introduction of foil-based packaging materials that incorporate a desiccant-coated laminate. These laminations eliminate the extra step and cost of adding a secondary desiccant device or substance to the package. Moreover, when the desiccant is embedded in the material, the package can be just big enough for the IVD. Early tests seem to show a higher desiccant effectiveness with the laminate than with discrete devices, owing to the drying influence being spread across the entire internal surface of the package rather than concentrated in one place.

Why didn't someone think of this earlier? They did, years ago, but the packaging machine did not exist that could seal through the desiccant layer to provide a sufficiently strong seal without overheating the packaged product. Many IVDs cannot be subjected to temperatures above 200°F without performance degradation. Heat-sealing process temperatures were as high as 500°F at the edge of the packages designed with desiccating materials of construction, which translated to internal package temperatures above the 200°F limit. These high temperatures would kill the device chemistry, essentially rendering the device worthless.

Continuous-motion packaging machines today can use platen heat-seal technology to control temperature and pressure precisely within ±1% when sealing packaging materials containing embedded-desiccant laminates. They can hold the set pressure and temperature for dwell times up to 2 seconds so that sealing can be effected with application of the lowest possible temperature and pressure and no impact on the enclosed IVD. Their continuous-motion configuration enables multiple products to be packaged at each cycle; output rates in some IVD applications reach up to 2400 packages per minute.

Conclusion

The IVD industry is ready to adopt the latest technology in packaging automation. Large-volume IVD manufacturers need it to replace past-generation approaches that are high in overhead so they can reduce their costs and improve margins. Manufacturers that produce a range of IVDs need it to improve manufacturing efficiency and extend product shelf life. Manufacturers of devices employing new IVD chemistries need it to ensure the accuracy and viability of their most sensitive diagnostic innovations. And everyone affected by FDA's validation requirements needs it to comply with accepted standards.

Device accuracy, packaging efficiency, manufacturing economy, regulatory satisfaction, process and optimization —packaging automation technology provides the means to attain these ideals.

Ray Johnson is a cofounder and is currently the president of Doyen Medipharm Inc. (Lakeland, FL), an international supplier of packaging machinery and contract packaging services. He can be reached at ray@doyennet.com.

Copyright ©2002 IVD Technology