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by Hank Rahe

Biotechnology seems to be the pathway to deliver many of the cures for diseases that have plagued mankind. The technology has made significant contributions to healthcare by providing protein-based products from other than natural sources.

The industry profile seems to reveal two tiers of companies. The first tier includes a large number of companies with relatively few employees that tend to be the innovators or discovery force behind new products. The second tier has been able to bring products to market and is made up of large pharmaceutical companies and a few biotechnology companies that were able to work their way through the regulatory maze and launch a product.

The innovator companies are constrained by both capital and regulatory expertise to take the products through the extensive and costly gauntlet leading to approval by the Food and Drug Administration (FDA). Industry data indicates that it will take well over $500 million and eight to nine years to successfully bring a product to market. As an alternate route, smaller companies seek a partner that has the resources to continue the journey to approval once a promising compound has been identified and synthesized.

This model for bringing biotechnology products to market can be viewed as good news / bad news. The good news is that important potentially profitable products have a better chance of getting to the consumer more quickly. The bad news is that products may be discarded from consideration more quickly, leaving the chance that an important compound may be overlooked in the race for market approval. The disconcerting thing about this scenario is a number of compounds targeted for a particular medical use have been proven to be very valuable in treating another medical condition, and this secondary use will in all likelihood be missed. The biotechnology segment, because of the two-tiered structure, seems to be at highest risk for this lost potential.

Requiring companies to rigorously test compounds for safety and efficacy before approval has established the U.S. FDA as the gold standard throughout the world. Without compromising this standard and given the cost of screening and testing, is there a way to take a second look at the discarded compounds in the hope of identifying a different targeted use?

A possible solution is to align the current resources such as life-science based universities, foundations focused on improving the health of mankind and the healthcare industry into an alliance, which, if properly focused, could bring a powerful force to bear on developing new products from discarded compounds. Each of the partners has essential resources to accomplish the objective.

The life-science based universities have the resources of research-based facilities supported by a student population interested in gaining experience and, in some cases, facilities. The foundations have funding focused toward improving the health and safety of mankind. The healthcare industry has created the front-end work on the compounds and has developed limited knowledge, which will jump-start the screening.

This type of alliance would create a win- win situation for all parties. The universities would gain financially by grants from the foundations, the sale of the compound and enhanced reputations as important academic institutions. An arrangement could be made to give companies that contribute the compounds first rights to buy them back. The foundations would gain by improved return on their goals, and healthcare companies would gain from additional research resources and ultimately bring more products to market.

Hank Rahe is director of technology at Contain-Tech in Indianapolis. He has over 30 years' experience in the healthcare industry, as well as four years in academia. He is an expert in the areas of conventional and advanced aseptic processing. He is the past chairman of the board of the International Society of Pharmaceutical Engineers, and is a member of the CleanRooms Editorial Advisory Board.

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by Robert P. Donovan

My May 2000 CleanRooms column used the non-volatile residue monitor (NRM) as an example of how one discipline can gain performance advantages by adopting technology from a distinctly different technology.

I'd like to continue this story but in another vein—the story of how the seemingly obvious performance advantages of the NRM have gone largely unappreciated in the semiconductor ultrapure water (UPW) business. This is, perhaps the application one would think most likely to appreciate the improved sensitivity and on-line compatibility offered by the NRM and, hence, the application in which it would prove most beneficial and popular.

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Part of the problem seems to be that the NRM measures a property not included in the traditional set of specifications for UPW.* It measures all the nonvolatile residue (NVR) in a liquid sample without regard to the residue's composition, source or other properties and expresses the result in terms of an equivalent concentration of potassium chloride in an aqueous solution. Thus, one gets a quantitative measure of water quality but no clue as to how to lower a currently measured value of the water's NVR. The composition of the measured NVR remains unidentified and can include a large number of possibilities. The manufacturer^1,2 lists the following potential contributors to NVR: dissolved silica, particles, colloidal silica, organics and both ionic and non-ionic impurities.

Consider each of these species.

Dissolved silica: While the NRM measures dissolved silica, its results haven't always correlated well with those of conventional, on-line silica analyzers using the molybdenum blue chemical reaction. Figure 1, however, shows that, under well-controlled conditions, the sensitivity of the NRM is superior to that of the conventional silica analyzer. Nonetheless, the conventional silica monitor, a significantly lower cost analyzer, continues to be the relied-on analyzer for this contaminant.

Particles: The NRM certainly counts particles—after all, its detector is a condensation particle counter—but it's hard to conceive of a water sample in which the particle concentration would be sufficiently high to dominate NVR. The concentration of aspirated water droplets is on the order of 10¹² per cm³ so that the particle concentration would have to be at least 10¹⁰ per cm³ in order to have any chance of being detected.

Light-scattering particle counters are better suited for analyzing UPW samples.

Colloidal silica: This term refers to polymeric aggregates of silica atoms, generally too small to be counted by light-scattering analyzers but not too small to be counted by the CPC of the NRM. Indeed this capability of the NRM is one of its unique strengths. As was true for particles, the number density of the colloids must be near that of the aspirated water droplets, but a solution that is 1 ppb by weight silica corresponds to about 1010 particles /cm³ of 5 nm colloidal silica particles.² No other analyzer, off- or online, can match this sensitivity for measuring colloidal silica.

Organics: Some organics are highly volatile and others, less so. The highly volatile species disappear with the water vapor in the drying section of the NRM. The nonvolatile organics remain behind and are counted. A third class of organics—those whose volatility depends on the drying temperature of the NRM, which can be adjusted between room temperature and 125 degrees Celsius—offers the intriguing possibility of being able to speciate organic contributions by noting the temperature signature of a contaminant. This potential capability has yet to prove of practical significance.

Ionic and non-ionic impurities: Detecting and measuring these contaminants is a real strength of the NRM. However, low cost resistivity cells also perform the measurement of conductive ions with high sensitivity. The NRM, however, also measures nonconductive salts, unlike a resisitivity cell.

Thus, in view of the foregoing, the NRM remains primarily a solution looking for a problem from the semiconductor UPW viewpoint. Its ability to detect colloidal silica online may be its best performance claim at present. Given the NRM's clever design, sensitivity and online capability, it seems it should play a more prominent role in UPW technology.

Robert P. Donovan is a process engineer assigned to the Sandia National Laboratories as a contract employee by L & M Technologies Inc., Albuquerque, NM. His Sandia project work is developing technology for recycling spent rinse waters from semiconductor wet benches.

References

1. Blackford, D. B., “The Measurement of Nonvolatile Residue in High-Purity Water,” J. Process Analytical Chemistry, vol. IV, Nos. 3,4, Winter 1998/1999, pp 92-98.
2. Wilbowo, J., F. Shadman and D. Blackford, “Measuring and Removing Dissolved and Colloidal Silica in Ultrapure Water,” MICRO 15 (5), May 1997, pp. 41-42, 44, 46 – 50.

Acknowledgement. I thank Dr. David Blackford, Fluid Measurement Technologies Inc., for his critique of this column and CT. Associates for Figure 1, made available by courtesy of FSI International.

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*ASTM D 5127-99 (Standard Guide for Ultra Pure Water Used in the Electronics and Semiconductor Industry) now lists “residue after evaporation” as a required UPW parameter and references D 5544 (Standard Test Method for On-Line Measurement of Residue After Evaporation of High-Purity Water), based on the NRM, for its measurement.

Kelly Sewell

MOUNT PROSPECT, IL—The effort to sunset Fed-Std 209 gained momentum in January, when the Institute for Environmental Science and Technology (IEST; Mount Prospect, IL) formally submitted its request to the U.S. General Services Agency (GSA) to retire the standard. The action has been a long time coming: IEST was first asked to make the recommendation to GSA in October 1999 [See, “ISO Committee turns up heat,” CleanRooms, December 1999, p.1].

According to Robert Mielke, IEST vice president for contamination control, IEST CC Working Group 100 decided at its May 2000 meeting to recommend to GSA that it no longer maintain Fed-Std-209. The GSA then requested copies of both ISO 14644-1, “Classification of air cleanliness,” and 14644-2, “Specifications for testing and monitoring to prove continued compliance with ISO 14644-1,” to consider as the federal standard's replacement. Those copies are now in GSA's possession. It is important to note that IEST only gives recommendations to the GSA, and doesn't have influence over when action is taken.

The GSA will now distribute the documents to government agencies currently using Fed-Std-209, asking if the agencies will make the move to support the ISO standard in favor of Fed-Std-209.

The agencies will have 60 days to review the documents. It is theoretically possible that some agencies might request an extension for further review, which would further delay the process.

“When the agencies' comments are sent back to GSA, they'll make a decision. If all the organizations say, 'Let's not maintain 209 anymore,' then that will happen,” Mielke says. “They may also turn around and say, 'we don't want to drop it' and we'll use it as is.”

However, Richard A. Matthews, chairman of chairman of the International Organization for Standardization Technical Committee ISO/TC 209, “Cleanrooms and associated clean environments,” says he's certain the ISO standards will be approved as a result of the Reagan Paperwork Reduction Act, which prohibits the U.S. government from creating or updating standards where a comparable standard (in this case, the ISO standard) exists.

Mielke predicts the Fed-Std 209 document may be sunset in 2001, possibly as soon as the third quarter. When the decision becomes official, CleanRooms will exclusively use the ISO 14644 classifications and cease the use of the Fed-Std-209 nomenclature.

Consumer education will take precedent in success

Chris Anderson

SCHAUMBURG, IL—Years ago, the names Listeria and E. coli were known only by food-safety scientists. Today, in the wake of numerous E. coli outbreaks and food product recalls caused by Listeria, they have become household words. And if more and more Americans are beginning to feel that the safety of the food they put on the table is a gamble, IBA Technologies Ltd., is placing a huge bet that these same consumers will welcome irradiated food into their homes.

IBA's first wager is its gamma irradiation plant here that recently received a Grant of Inspection by the USDA to process beef, pork and poultry products. The existing facility has provided irradiation services for 20 years notably in the food packaging, spices and medical device industries and is one of only a handful of such operations approved to process meat.

The irradiation process kills pathogens and enzymes by exposing products to measured doses of radiant energy—either electrons, gamma rays or x-rays. But the big question is whether large meat processors will jump to have their products irradiated, especially when consumers' understanding and comfort with the sanitation method is still in question.

“Of the processors I have talked with, we have a number of very large companies that are prepared to be number two to market,” says Chip Colonna, vice president of perishable food of IBA's Memphis, TN-based Food Safety division.

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Despite endorsements of irradiation from the World Health Organization, The American Medical Association and the Centers for Disease Control and Prevention, irradiation appears to have an uphill battle in the arena of public opinion. “I think if you asked people at a cocktail party if they would eat irradiated foods, the first visions some would have is of Three Mile Island and radioactivity,” says Colonna. “That is just not the case. You get more radiation simply by going outside than you do from irradiated foods.”

Jeffrey Barach, vice president of the National Food Processors Association (Washington, DC), says much of the resistance to irradiated products is based on a lack of understanding and information. “Our focus groups show that after viewing an educational video, people understand the benefits provided by irradiation,” he says.

In addition, irradiation providers would like to find an alternate term for the process as they believe the name itself gives rise to many of the public's fears. “Cold pasteurization” has been suggested, though Barach says there is not unanimous agreement among food processors on using the term.

Aside from meat and poultry—products that have been approved for irradiation for less than two years—the FDA is expected to approve irradiation of ready-to-eat foods such as sandwich meats, hot dogs and bagged salads early this year.

When that happens, IBA will be ready.

It's newest facility, an e-beam and x-ray irradiation plant in Bridgeport, NJ, will soon become operational. “We're viewing that facility as a regional service center and that will allow companies in the Northeast to run test market quantities,” says Colonna.

Continuing its aggressive push, IBA announced in late January a deal with cold storage giant AmeriCold Logistics to construct an irradiation plant inside the nation's largest cold storage facility in Carthage, MO. “Irradiation is a process that many of our customers are evaluating,” says AmeriCold CEO Dan McNamara in a statement announcing the deal. “As the leading cold storage provider in the U.S., we believe that AmeriCold Logistics is in a good position to assist the food industry by providing them with access to improved food safety technology.”

All of which fits with IBA's grand vision. “As larger processors look into irradiation, they are going to look for facilities that can either attach to, or are right next to, their plants or distribution facilities,” says Colonna.

Those days may be some time off. “I think we will see a slow, steady build up of irradiated products on the market,” says Barach. “First of all, there are not that many facilities in operation right now to provide the service. Second, I think there are some processors who will choose to continue with their traditional processing methods. There is some division in the industry on this issue.”